The present invention, in some embodiments thereof, relates to mammalian embryonic pulmonary cells and, more particularly, but not exclusively, to the use of same for therapeutic applications.
Respiratory diseases are a major cause of mortality and morbidity, ranked by the world health organization as second most in incidence, prevalence, morbidity, mortality and cost. Most currently available therapies only slightly improve the quality of life of lung disease patients, and do not prevent the loss of gas-exchange surface, which is a major consequence of progression in a variety of pulmonary pathologies. Thus, currently, the only definitive treatment for end-stage lung disease is the replacement of the damaged organ, but many patients die while on the waiting list due to a severe shortage of organs for transplantation.
Previous studies defined “optimal windows” for transplantation of human and pig embryonic precursors of different organs. These “optimal windows” for transplantation were defined by three parameters: lack of risk for teratoma, functional properties of the growing tissue, as well as low immunogenicity. For example, implantation into SCID mice of different pig embryonic precursor tissues, revealed distinct time ‘windows’ during which the tissue exhibits properties suitable for transplantation, with kidney and liver exhibiting optimal properties at 28 days while the lung ‘window’ was shown to occur much later, at 56 days, of porcine gestational age [Eventov-Friedman S. et al., Proc Nat Acad of Sciences. (2005) 102(8): 2928]. Studies using pig pancreatic precursor tissue suggested its optimum at 42 days, at which time this tissue demonstrates marked ability to correct streptozotocin-induced hyperglycemia in immunosuppressed mice, and more recently, in non-human primates. Moreover, recent studies have shown that transplantation of pig embryonic spleen tissues, harvested at specific gestational time points, are able to correct hemophilia in FVIII deficient mice.
During the past decade, the potential curative role of stem cell based therapies has been extensively investigated. Recent findings suggest that early progenitors derived from adult tissues, such as the bone marrow or from the umbilical cord blood, amniotic fluid or placenta, including mesenchymal stem cells, endothelial progenitors or circulating fibrocytes and a variety of other populations, could structurally engraft and differentiate as airways and alveolar epithelial cells or as vascular endothelial or interstitial lung cells and could be utilized in repair and regeneration of injured or diseased lungs [Baber S R et al., American Journal of Physiology-Heart and Circulatory Physiology. (2007) 292(2): H1120; Weiss D J. Pulm Pharmacol Ther. (2008) 21(4):588-94; Weiss D J et al., Proceedings of the American thoracic society: Am Thoracic Soc; (2008) p. 637; Sueblinvong V and Weiss D J. Translational Research. (2010) 156(3): 188-205]. However, lack of significant epithelial transdifferentiation, the extremely complex structure of the lung, comprised of more than 40 different cell types, and a low engraftment rate of transplanted cells in the lung, in different experimental models, represent a major challenge.
Additional background art includes:
PCT Publication No. WO 2006/038211 relates to methods of providing a pancreatic, lymphoid/hematopoietic or pulmonary organ and/or tissue function to a mammalian subject. The method comprising transplanting into the subject a developing mammalian pancreatic, lymphoid/hematopoietic or pulmonary organ/tissue graft, respectively. The pulmonary graft disclosed in WO 2006/038211 is at a developmental stage essentially corresponding to that of a porcine pulmonary organ/tissue at a gestational stage selected from a range of about 42 to about 80 days of gestation.
PCT Publication No. WO 2004/078022 relates to methods of treating a disorder associated with pathological organ or tissue physiology or morphology. The method is effected by transplanting into a subject a mammalian organ or tissue graft (e.g. renal, pancreatic, hepatic, cardiac or lymphoid organ or tissue graft) selected not substantially expressing or presenting at least one molecule capable of stimulating or enhancing an immune response in the subject.